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Microbiota coordinate day-to-day gut innate immunity with circadian clock, feeding rhythms

Reuters Health - 11/08/2021 - Levels in the gut of a natural antimicrobial molecule fluctuate according to a circadian rhythm prompted by intestinal microbiota, studies in mice show.

"We did not anticipate such strong circadian patterns in gut innate immunity," Dr. Lora Hooper of UT Southwestern in Dallas told Reuters Health by email. "I guess I assumed that given the large numbers of bacteria that normally colonize the intestine, that innate immunity would always be 'on' to the maximum extent possible. This is clearly not the case, suggesting that the system is geared more toward dealing with 'foreign' bacteria associated with food."

"The other surprise was that these circadian patterns in gut innate immunity were actually triggered by a member of the gut microbiota, segmented filamentous bacteria (SFB)," she explained. "These bacteria respond to the normal rhythmic feeding patterns of mice by attaching and then detaching from the gut epithelium during the course of the day-night cycle. This triggers a circadian immunological response that leads to the rhythmic production of antimicrobial proteins."

"We had no idea the system would be this complicated," she acknowledged.

As reported in Cell, in a series of experiments in mice, Dr. Hooper and colleagues looked for rhythms in the expression of natural antimicrobial agents produced in the gut to fight foodborne illness.

In normal lab mice, one of these antimicrobial molecules - regenerating islet-derived protein 3g (REG3G) - was more abundant at night, when these nocturnal animals are active, and less so during the day, when the mice sleep.

Mice with cycling amounts of REG3G had large gut-resident populations of SFB - microbes present in rodents, nonhuman primates, and humans that can attach to the intestinal lining and change the hosts' gene activity.

Further experiments showed that these bacteria attached to the mice's intestinal lining during feeding, and when they did so, REG3G production ramped up in the intestines.

This cycling affected ability of the mice to fight off infection. Normal mice infected with salmonella typhimurium had higher bacterial burdens and mortality if they were exposed at sunset than at sunrise.

By contrast, genetically altered mice that couldn't produce antimicrobial proteins such as REG3G had high rates of bacterial burden and death regardless of what time of day or night they were infected.

The authors write, "Mechanistically, rhythmic SFB attachment activated an immunological circuit involving group 3 innate lymphoid cells. This circuit triggered oscillations...that produced rhythmic antimicrobial protein expression and caused resistance to salmonella typhimurium infection to vary across the day-night cycle. Thus, host feeding rhythms synchronize with the microbiota to promote rhythms in intestinal innate immunity that anticipate exogenous microbial exposure."

Dr. Hooper said, "Our findings were strictly in mice, so at this point we don't know whether a similar system exists in humans. Thus, it's too soon to speculate on whether our findings might have implications for people with digestive disorders, but it's certainly something we're interested in exploring further."

Immunologist Dr. Christoph Thaiss, Assistant Professor, Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania commented on the study in an email to Reuters Health. "Previous studies have identified diurnal rhythms in the microbiome that are regulated by times of food intake, and this new study links circadian host-microbiome interactions to the antimicrobial response and susceptibility to enteric infection. It demonstrates that the intestinal ecosystem is differentially susceptible to microbial invasion over the course of a day."

"This is evolutionarily plausible," he said, "since the introduction of food-borne pathogens is linked to times of food consumption, and thus the microbiome and host may have developed strategies to anticipate and circumvent pathogen invasion at different times of the day."

"It would be interesting if and how this new discovery can be applied to other intestinal pathogens," he said. "Do all enteric pathogens show differential ability to invade the gut at different times of the day? Furthermore, it will be interesting to explore whether rhythmicity in the antimicrobial response exists in humans."

"The realization that risk for enteric infection is highly circadian due to the cross-regulation of the gut microbiota and the intestinal antimicrobial system may inform pharmacological approaches that support the antimicrobial response," he noted. "The concept of chronopharmacolgy - which is aimed at optimizing pharmacology based on knowledge about circadian properties of drugs - is a highly underutilized strategy that is able to maximize efficiency and reduce adverse side effects of numerous drugs."

SOURCE: https://bit.ly/3CIqkpO Cell, online July 28, 2021.

By Marilynn Larkin

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